Human melanocytes are neural crest derived cells that perform a unique function in the skin. While they are a minority of the population of the epidermis, they are responsible for the majority of photoprotection of the skin from ultraviolet radiation (UVR) through the production and transfer of melanin to keratinocytes [1]. Melanocytes, or their stem cells, are also progenitor cells for the most deadly of skin cancers, melanoma, which arises as a step wise progression from benign, to minimally invasive, to metastatic tumor [2]. Paracrine factors, produced primarily by keratinocytes, but also by fibroblasts, control multiple melanocyte functions, including dendricity, migration, growth and pigmentation, and also regulate normal homeostasis of melanocytes in the skin. Disordered of these growth factors, their receptors, or signaling pathways, are implicated in melanoma progression, as well as in disordered pigmentation [3]. Therefore, discovery of new or novel paracrine factors, and defining receptors and signaling pathways stimulated by these factors, are important to understanding melanocyte regulation in the skin, and melanoma tumor progression. Semaphorins are a large family of proteins that were originally identified in the nervous system, and are critical regulators of axon guidance. During the last 5 years, numerous reports show that semaphorins and their receptors (Plexins and Neuropilins) are widely distributed and regulate multiple biologic processes, including cell adhesion and migration, neurite extension, immune function, organogenesis, and tumor progression. Our published and preliminary data show a previously unrecognized role for semaphorins in human melanocyte function. Semaphorin 4D and semaphorin 7A regulate multiple cellular processes in other cell types, including neurite outgrowth and retraction, tumor progression and immune modulation [4]. We are the first to show that semaphorin 4D (Sema4D) and semaphorin 7A (Sema7A) control melanocyte attachment, spreading and dendricity, which are critically important for normal skin pigmentation. Further, our data suggest a potential role for Sema4D and Sema7A in melanoma progression, because their cognate receptors (Plexin B1 and Plexin C1 respectively) are either reduced or absent in melanoma. Finally, our preliminary data indicate a novel role for Sema4D in downregulation of c-Met receptor activation, a receptor critically important for melanocyte cell growth, migration, differentiation, and melanoma progression. We hypothesize that Sema4D and Sema7A regulate melanocyte migration and dendrite formation through stimulation of intracellular signaling pathways that include the GTP binding proteins Ras, Rho, Rac, integrins and LIM kinase- cofilin pathways. We predict that effects of Sema7A are mediated by a balance between 1- integrin and cofilin activation. We predict that effects of Sema4D are mediated by a balance between c-Met receptor inhibition and Plexin B1 activation. Finally, we predict that loss of Plexin B1 and Plexin C1 expression contribute to melanoma progression through enhanced melanoma cell growth, migration, and survival due to loss of c-Met receptor inhibition and coflin activation, respectively. PUBLIC HEALTH RELEVANCE. Identification of new growth factors that regulate human melanocyte function is important for understanding pigmentation of the skin, and in the transformation of benign melanocytes to malignant melanoma. We have identified two proteins, Semaphorin 4D and Semaphorin 7A, which stimulate human melanocyte function through the receptors Plexin B1 and Plexin C1 respectively. Further, we show that both of these receptors are reduced or absent in melanoma cell lines, and, in the case of Plexin C1, in melanoma in vivo. The goal of this project is to define how Semaphorins signal through Plexin receptors, and to understand the mechanisms by which loss of Plexin receptor expression contributes to melanoma metastasis.